Jaw-Tumor Hyperparathyroidism Syndrome as Reproductive Disease Model

颌骨肿瘤甲状旁腺功能亢进综合征作为生殖疾病模型

• 批准号: 8736948
• 负责人: Erin Wolff
• 金额: $ 1.92万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736948
• 关键词: Adenocarcinoma; Adenofibroma; Adenomyoma; Adenosarcoma; Adult; Affect; Anemia; Aromatase; Aromatase Inhibitors; Benign; Cell Cycle Progression; Cell Line; Cell Survival; Cells; Cervical; Cervix Uteri; Clinical; Common Neoplasm; Complex; Critical Pathways; Cyst; Defect; Disease; Disease model; Electrocoagulation; Elements; Embryonic Development; Endometrial; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrial Stromal Cell; Endometrium; Epithelial; Evaluation; Exhibits; Family; Family Study; Family member; Female; Fibroid Tumor; Functional disorder; Fundus; Genes; Genetic Transcription; Genets; Genotype; Growth Factor; Gynecologic; High Prevalence; Histologic; Histones; Human; Hyperparathyroidism; Hyperplasia; Hysterectomy; Hysteroscopy; Image; In Vitro; Infant; Intrauterine Devices; Jaw; Knockout Mice; Laboratories; Lesion; Life; Magnetic Resonance Imaging; Malignant Neoplasms; Medical; Menorrhagia; Menstrual cycle; Methylation; Missense Mutation; Molecular Genetics; Mucous body substance; Mus; Mutate; Mutation; Myoma; Myometrial; Nuclear Localization Signal; Operating Rooms; Operative Surgical Procedures; Parathyroid Neoplasms; Pathology; Patients; Pattern; Phenotype; Physical Examination; Physiological; Polyps; Postoperative Period; Pregnancy; Progesterone; Property; Proteins; RNA Polymerase II; Reporting; Reproduction; Resistance; Role; Seedling; Signal Transduction; Source; Staining method; Stains; Structure; Symptoms; Syndrome; System; Tissue Sample; Transvaginal Ultrasound; Tumor Suppressor Genes; Tumor Suppressor Proteins; Uterine Lesion; Uterine Neoplasms; Uterine Polyp; Uterine cavity; Uterine hemorrhage; Vaginal delivery procedure; Woman; bone; experience; follow-up; improved; in utero; mutant; novel; pregnant; reproductive; tumor

A 26 year old nulligravida woman from a family with HPT-JT was referred for life-long menorrhagia resulting in anemia. Members of her family were known to carry a L95P missense mutation in CDC73/HRPT2, and several were affected with HPT-JT. The patient desired management of her menorrhagia and the ability to conceive. The patient was genotyped and found to be heterozygous for a germline L95P parafibromin missense mutation. Physical examination was notable for a large everted external cervical os. Transvaginal ultrasound and magnetic resonance imaging demonstrated an enlarged endometrial lining with thickening of the junctional zone. Operative hysteroscopy revealed a uterine cavity filled with atypical, fibrous endometrial polyp-like structures which extended from the fundus and down through the cervix. The polyps were surgically removed with electrocautery and multiple mucous filled cysts were seen. Histologic examination of these polypoid structures revealed benign uterine adenomyomas. A new progesterone IUD was placed in the uterine cavity in the operating room for management of menorrhagia. Five months later the patient presented with persistence of menorrhagia. Staining for aromatase was then performed on her histologic tissue samples from the prior surgery. This staining revealed an over-expression of aromatase within her adenomyomas as compared to normal controls without adenomyomas. The patient was started on an aromatase inhibitor. Upon follow up six months after the aromatase inhibitor was started, the patient noted decreased uterine bleeding and her endometrial lining was thin at 4mm. Post-operatively, the patient received medical therapy with an aromatase inhibitor and a progesterone intrauterine device. This treatment was continued for a total of ten months resulting in continued improvement in her symptoms. The patient desired pregnancy and a follow-up hysteroscopy documented dramatic improvement in the uterine cavity with a few smaller polyps the largest of which was 3mm. The IUD and the remaining small polyps were surgically removed. The aromatase inhibitor was discontinued three months after surgery and the patient became spontaneously pregnant with her next ovulatory cycle. She had an uncomplicated pregnancy resulting in a term spontaneous vaginal delivery of a 4479gm female. Imaging demonstrated an enlarged endometrial lining and thickening of the junctional zone. At operative hysteroscopy, multiple atypical endometrial polyp-like lesions filled the entire uterine cavity and were removed. Histologic evaluation demonstrated the lesions to be adenomyomas with an abundance of aromatase expression. Postoperative treatment included an aromatase inhibitor. The patients menorrhagia, which had previously been resistant to progesterone IUD therapy, resolved with the aromatase inhibitor. After ten months of this treatment, the aromatase inhibitor was discontinued and a repeat hysteroscopy revealed a markedly improved uterine cavity. The patient subsequently became pregnant on her first natural cycle and delivered a healthy term infant. To our knowledge, assessment of aromatase expression in the uterine pathology of HPT-JT has not been reported. As part of this project, the use of aromatase inhibitors resulted in marked clinical improvement, decreased menorrhagia, and the ability to conceive. This may represent a novel therapy for the medical therapy of benign uterine lesions in women with HPT-JT. In addition to developing novel clinical therapies for this disorder, we have utilized this rare condition to study gynecologic conditions in the laboratory. Currently, efforts are underway to create novel in vitro cell lines to study this disorder. These cell lines could become important systems used to study benign endometrial diseases, as well as atypical uterine malignancies, where cells lines for in vitro study are lacking.

一名来自HPT-JT家族的26岁未成年妇女被转诊为终生月经过多导致贫血。已知她的家人携带CDC73/HRPT2的L95P错义突变，其中几人感染了HPT-JT。病人希望月经过多和怀孕的能力得到处理。患者进行了基因分型，发现L95P副纤维蛋白错义突变为杂合子。 体格检查发现有一个大的外翻的颈外翻。经阴道超声和磁共振成像显示子宫内膜层扩大，交界区增厚。宫腔镜检查显示宫腔内充满了非典型的、纤维性的子宫内膜息肉样结构，这些结构从眼底向下延伸至宫颈。息肉用电灼术切除，可见多个粘液充盈的囊肿。这些息肉样结构的组织学检查显示为良性子宫腺肌瘤。为了治疗月经过多，在手术室的宫腔内放置了新的孕酮宫内节育器。 五个月后，患者出现持续性月经过多。然后对她先前手术的组织标本进行芳香酶染色。这一染色显示，与非腺肌瘤的正常对照组相比，她的子宫腺肌瘤中芳香酶的过度表达。患者开始服用芳香酶抑制剂。芳香酶抑制剂开始治疗6个月后，患者注意到子宫出血减少，子宫内膜衬里变薄，厚度为4 mm。 术后，患者接受了芳香酶抑制剂和黄体酮宫内节育器的药物治疗。这种治疗总共持续了十个月，使她的症状持续改善。患者想要怀孕，随后的宫腔镜检查发现宫腔明显改善，有几个较小的息肉，最大的息肉有3毫米。宫内节育器和剩余的小息肉被手术取出。芳香酶抑制剂在手术后三个月停止使用，患者自然怀孕，进入下一个排卵周期。她有一次不复杂的妊娠，导致一名4479克重的女性足月自然阴道分娩。 影像显示子宫内膜层增大，交界区增厚。在手术宫腔镜检中，多发性非典型子宫内膜息肉样病变充满整个宫腔并被切除。组织学评估显示病变为腺肌瘤，有丰富的芳香酶表达。术后治疗包括芳香酶抑制剂。患者月经过多，之前对黄体酮宫内节育器治疗有抵抗力，通过芳香酶抑制剂解决。经过10个月的治疗，芳香酶抑制剂停用，重复的宫腔镜检查显示宫腔明显改善。患者随后在她的第一个自然周期怀孕，并生下了一个健康的足月婴儿。 据我们所知，芳香化酶在HPT-JT子宫病理中的表达评估尚未见报道。作为该项目的一部分，芳香酶抑制剂的使用显著改善了临床，减少了月经过多，并提高了受孕能力。这可能为HPT-JT妇女良性子宫病变的药物治疗提供了一种新的治疗方法。 除了为这种疾病开发新的临床治疗方法外，我们还利用这种罕见的情况在实验室研究妇科疾病。目前，正在努力创造新的体外细胞系来研究这种疾病。这些细胞系可能成为研究良性子宫内膜疾病以及缺乏体外研究细胞系的不典型子宫恶性肿瘤的重要系统。